1. Field of the Invention
The present invention is a process, including intermediates, to produce latanoprost, a pharmaceutical agent useful in treating ophthalmic conditions.
2. Description of the Related Art
U.S. Pat. No. 5,422,368 discloses latanoprost (Example 2) and its usefulness as an ophthalmic agent. The patent discloses a process (Example 2) to prepare latanoprost and two closely related compounds.
There are very limited numbers of examples of reductions of xcex1,xcex2-unsaturated enones with chlorodiisopinocampheylborane. J. Am. Chem. Soc., 110(5), 1539-46 (1988) describes a single example of reduction of an acyclic aryl enone, 4-phenyl-3-buten-2-one, with chlorodiisopinocampheylborane giving an 81% eantiomeric selectivity, and no examples of simple acyclic non-aryl conjugated enones.
Bull. Korean Chem. Soc., 15(12), 1033-4 (1994) addresses the issue of 1,2 versus 1,4 reduction with chlorodiisopinocampheylborane but did not discuss the enantioselectivity or diastereoselectivity of the reductions.
Tetrahedron Letters 1067-1070 (1976) discloses a cyclopentane diol-acid where the side-chain did not contain any aromatic functionality.
Disclosed is a compound of the formula (VI) 
where:
(1) R3 is xe2x80x94H and R4 is xe2x80x94H,
(2) R3 is xe2x80x94H and R4 is xe2x80x94Oxe2x80x94CH3 and
(3) R3 and R4 are taken together to form a five member ring attached to the 3- and 4-positions of the phenyl ring where the second ring from the R3-position to the R4-position is xe2x80x94CHxe2x95x90CHxe2x80x94Oxe2x80x94 and
where . . .  is a single or double bond and pharmaceutically acceptable salts thereof.
Also disclosed is a process for the preparation of a 15(S)-prostaglandin intermediate selected from the group consisting of compound (IV) 
where R3, R4 and . . .  are as defined above and where X11 is phenyl or phenyl substituted with one thru three C1-C4 alkyl, one thru three C1-C4 alkoxy, one phenyl, one thru three xe2x80x94F, xe2x80x94Cl, xe2x80x94Br and xe2x80x94I and compound (XVIII) 
where X11 is defined above which comprises:
(1) contacting a compound selected from the group consisting of compound (III) 
where R3, R4, X11 and . . .  are as defined above or compound (XVII), respectively, 
where X11 is defined above with (xe2x88x92)-chlorodiisopinocampheylborane while maintaining the reaction mixture temperature in the range of from about xe2x88x9250xc2x0 to about 0xc2x0 and
(2) contacting the reaction mixture of step (1) with a boron complexing agent.
Latanoprost (XVI) is known, see U.S. Pat. No. 5,422,368, Example 2.
The process of the present invention is set fort in CHARTs A and B and in EXAMPLES 1-12.
The enone (III), as well as the other compounds of the invention, has three possibilities for the substitution on the phenyl ring of the bottom side chain. These are where R3 and R4 are:
(1) R3 is xe2x80x94H and R4 is xe2x80x94H which gives phenyl,
(2) R3 is xe2x80x94H and R4 is xe2x80x94Oxe2x80x94CH3 which give 4-methoxyphenyl and
(3) R3 and R4 are taken together to form a five member ring attached to the 3- and 4-positions of the phenyl ring where the second ring from the R3-position to the R4-position is xe2x80x94CHxe2x95x90CHxe2x80x94Oxe2x80x94;
where . . .  is a single or double bond and
where X11 is phenyl or phenyl substituted with one thru three C1-C4 alkyl, one thru three C1-C4 alkoxy, one phenyl, one thru three xe2x80x94F, xe2x80x94Cl and xe2x80x94Br. It is preferred that R3 and R4 are both xe2x80x94H. It is preferred that X11 is phenyl.
The enone (III) must be protected at the C-11 position as is known to those skilled in the art. It is preferred that for the protecting group xe2x80x94COxe2x80x94X11, X11 is phenyl or phenyl substituted with one thru three C1-C4 alkyl, one thru three C1-C4 alkoxy, one phenyl, one thru three xe2x80x94F, xe2x80x94Cl and xe2x80x94Br. With regard to the (xe2x88x92)-chlorodiisopinocampheylborane reduction of the xcex1,xcex2-unsaturated enone (III) the reduction can be performed in any chemically inert solvent that adequately dissolves the enone (III). Suitable solvents include THF, methylene chloride and DME and mixtures thereof. MTBE and toluene alone are not operable. The use of a cosolvent, such as hexane, heptane, isooctane or similar hydrocarbons is not necessary but is preferred. This is important since (xe2x88x92)-chlorodiisopinocampheylborane is available commercially as a solution in these solvents. MTBE and toluene can be used as the cosolvent. The nature of the solvent has virtually no effect with regard to the 15(S)/15(R) ratio in the product. It is preferred that from about 3 to about 4 equivalents of (xe2x88x92)-chlorodiisopinocampheylborane be used; it is more preferred that at least 3.5 equivalents of (xe2x88x92)-chlorodiisopinocampheylborane be used. With fewer equivalents the reaction is incomplete; there is no improvement in rate or selectivity with more equivalents. When the (xe2x88x92)-chlorodiisopinocampheylborane is contacted with the xcex1,xcex2-unsaturated enone (III), the temperature should be maintained less than 0xc2x0. It is preferred that the temperature be maintained at less than xe2x88x9220xc2x0; it is more preferred that the temperature be maintained in the range of from about xe2x88x9235 to about xe2x88x9245xc2x0. Above xe2x88x9235xc2x0 the selectivity decreases and below about xe2x88x9245xc2x0 the rate becomes too slow to be practical.
When the reaction is complete, the excess (xe2x88x92)-chlorodiisopinocampheylborane must be destroyed by use of a boron complexing agent which is selected from the group consisting of water, C1-C6 alcohols and diols, ethanolamine, diethanolamine, triethanolamine and mixtures thereof. It is preferred that the boron complexing agent be group be water and diethanolamine; it is more preferred that the complexing agent be water.
It is preferred that prior to step (2), the reaction mixture of step (1) is contacted with a readily reducible aldehyde or ketone. It is preferred that the readily reducible aldehyde or ketone is selected from the group consisting of C1-C6 aldehydes and ketones and benzaldehyde; it is more preferred that the readily reducible aldehyde or ketone is acetone or methylethylketone. When adding the boron complexing agent it is preferred that a base also be added. It is preferred that the base is selected from the group consisting of carbonate, bicarbonate, mono- di- and tri-C1-C6 alkylamines, pyridine and pyridine substituted with C1-C4 alkyl; it is more preferred that the base be bicarbonate or carbonate. It is even more preferred that the base be bicarbonate.
Either prior to, or after, step (2), it is preferred to warm the reaction mixture to about 15 to about 25xc2x0. It is preferred that the reaction mixture is warmed from about 1 to about 3 hr.
Latanoprost (XVI) is known to be useful as an ophthalmic pharmaceutical agent, see U.S. Pat. Nos. 5,296,504 and 5,422,368. In addition, International Publication WO98/30900 discloses that latanoprost (XVI) is useful in treating another ophthalmic condition, myopia.
The process of CHART B (and EXAMPLEs 11 and 12) starts with a known enone (XVII) and transforms it to the 15-alcohol (XVIII) intermediate known to be useful in the production of pharmaceutically useful prostaglandins, see Tetrahedron Letters, 1076-1070 (1976) and J. Am. Chem. Soc. 92, 397-8 (1970). The process of the reduction of the non-aryl xcex1,xcex2-unsaturated ketone (XVII) is analogous to the reduction of the aryl xcex1,xcex2-unsaturated ketone (III).
The products where R3 is xe2x80x94H and R4 is xe2x80x94Oxe2x80x94CH3 and where R3 and R4 are taken together to form a five member ring attached to the 3- and 4-positions of the phenyl ring where the second ring from the R3-position to the R4-position is xe2x80x94CHxe2x80x94CHxe2x80x94Oxe2x80x94 are also known to be useful pharmaceutical agents. Those two agents can also be prepared by the process of the present invention.
The definitions and explanations below are for the terms as used throughout this entire document including both the specification and the claims.
All temperatures are in degrees Celsius.
Latanoprost (XVI) refers to (5Z)-(9CI)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoic acid 1-methylethyl ester. It is also known as 17-phenyl-18,19,20-trinor-PF2xcex1 isopropyl ester.
MTBE refers to methyl t-butyl ether.
TLC refers to thin-layer chromatography.
THF refers to tetrahydrofuran.
THP refers to tetrahydropyranyl.
Saline refers to an aqueous saturated sodium chloride solution.
Chromatography (column and flash chromatography) refers to purification/separation of compounds expressed as (support, eluent). It is understood that the appropriate fractions are pooled and concentrated to give the desired compound(s).
CMR refers to C-13 magnetic resonance spectroscopy, chemical shifts are reported in ppm (xcex4) downfield from TMS.
NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemical shifts are reported in ppm (xcex4) downfield from tetramethylsilane.
TMS refers to trimethylsilyl.
xe2x88x92xcfx86 refers to phenyl (C6H5).
MS refers to mass spectrometry expressed as m/e, m/z or mass/charge unit. [M+H]+ refers to the positive ion of a parent plus a hydrogen atom. EI refers to electron impact. CI refers to chemical ionization. FAB refers to fast atom bombardment.
HRMS refers to high resolution mass spectrometry.
Pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.
psi refers to pounds per square inch.
When solvent pairs are used, the ratios of solvents used are volume/volume (v/v).
When the solubility of a solid in a solvent is used the ratio of the solid to the solvent is weight/volume (wt/v).
DIBAL refers to diisobutyl aluminum hydride.
THAM refers to tris(hydroxymethyl)aminomethane.